Disparate osteogenic response of mandible and iliac crest bone marrow stromal cells to pamidronate.
OBJECTIVE
Long-term administration of intravenous bisphosphonates like pamidronate is associated with jaw osteonecrosis but axial and appendicular bones remain unaffected. Pathogenesis of bisphosphonate-associated jaw osteonecrosis may relate to skeletal site-specific effects of bisphosphonates on osteogenic differentiation of bone marrow stromal cells (BMSCs) of orofacial and axial/appendicular bones. This study evaluated and compared skeletal site-specific osteogenic response of mandible (orofacial bone) and iliac crest (axial bone) human BMSCs to pamidronate.


METHODS
Mandible and iliac crest BMSCs from six normal healthy volunteers were established in culture and tested with pamidronate to evaluate and compare cell survival, osteogenic marker alkaline phosphatase, osteoclast differentiation in co-cultures with CD34+ hematopoietic stem cells, gene expression of receptor activator of NFkappaB ligand (RANKL) and osteoprotegerin, and in vivo bone regeneration.


RESULTS
Mandible BMSCs were more susceptible to pamidronate than iliac crest BMSCs based on decreased cell survival, lower alkaline phosphatase production, and structurally less organized in vivo bone regeneration. Pamidronate promoted higher RANKL gene expression and osteoclast recruitment by mandible BMSCs.


CONCLUSIONS
Mandible and iliac crest BMSC survival and osteogenic differentiation are disparately affected by pamidronate to favor dysregulated mandible bone homeostasis.
Stefanik
D
D
Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
Sarin
J
J
Lam
T
T
Levin
L
L
Leboy
P S
PS
Akintoye
S O
SO
D000469:Alkaline Phosphatase / Q000187:drug effects / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects*; D001861:Bone Regeneration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004164:Diphosphonates / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007085:Ilium / Q000166:cytology* / Q000187:drug effects; D008334:Mandible / Q000166:cytology* / Q000187:drug effects; D009928:Organ Specificity; D010012:Osteogenesis / Q000187:drug effects; D000077268:Pamidronate; D053245:RANK Ligand / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects
D018952:Antigens, CD34; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D053245:RANK Ligand; D000469:Alkaline Phosphatase; D000077268:Pamidronate